Paracetamol (p-acetylaminophenol) is a common analgesic and antipyretic drug that is used for the relief of fever, headaches, and other minor aches and pains. It is a major ingredient in numerous cold and flu medications and many analgesics prescriptions. The drug is popularly used as an analgesic and antipyretic, and as a pain reliever in acute pain and chronic pain. Paracetamol injections are used for the management of acute febrile conditions as well as analgesic for management of acute pain including post operative pain.
Pharmaceutical preparations comprising paracetamol to be administered orally are well known. It is however well accepted that concentrated parenteral pharmaceutical compositions containing paracetamol in solution offer several advantages over solid compositions as they provide rapid onset of pharmacologic action, since, unlike the oral compositions, which first have to first disintegrate and dissolve in the gastrointestinal tract to enable absorption.
There are two classes of conventional parenteral formulations of paracetamol available in the market.
The first one comprises 150 mg/ml paracetamol presented in 2 ml solution. This dosage form provides 300 mg of paracetamol per dose which is much below the minimum therapeutic dose of 500 mg. These have high viscosity of about 24.80 cps causing pain when administered by the intramuscular route. Further this dosage form has the additional disadvantage of delivering sub-therapeutic quantities.
The other parenteral formulation comprises aqueous solutions of paracetamol in a concentration of 10 mg/ml, presented in 50 ml and 100 ml vials providing 500 mg and 1000 mg of paracetamol per vial respectively. These dosage forms are administration only by intravenous infusion and obviously unsuitable for intramuscular route. Such dosage forms are not suitable for use in Out-Patient-Department (OPD) settings. Concurrent administration of these dosage forms with other intravenous fluids, e.g. Ciprofloxacin I.V. infusion, is inconvenient. Further, manufacture of these dosage forms need additional infrastructure, larger storage space and bulk transport adding to the end cost of these products.
There is therefore an unmet need to provide high concentration paracetamol containing injectable compositions that can deliver the therapeutic dosage (500 mg) in single dose for intramascular administration without causing pain to the patient. Further there is a need for such high concentration dosage forms that can be adapted for administration with I.V. infusions
PCT/IN2009/000038 relates to aqueous, stable pharmaceutical composition comprises paracetamol for parenteral administration, wherein the concentration of paracetamol in the composition is 10 mg/1 ml. The dosage form is suitable only for intravenous infusion.
PCT/IB2008/003217 discloses stable aqueous formulations containing 10 mg/1 ml of acetaminophen exclusively to be administered by intravenous infusion as well as processes for their preparation.
PCT/NL2004/000819 relates to a composition with the aqueous state for the administration in perfusion of at least an active principle, especially pharmacological such as paracetamol.
PCT/GR2001/000047 discloses stable solutions of paracetamol for parenteral administration wherein the concentration of paracetamol is 150 mg/1 ml. These need to be administered in multiple doses to achieve the therapeutic dosage of 500 mg and hence are not suitable.
PCT/EP1999/005486 describes a pharmaceutical composition, characterized in that: a) it comprises i) paracetamol, ii) from 1 to 4 parts by volume of a low molecular weight alcohol for each part by weight of paracetamol, and iii) from 1 to 5 parts by volume of a polyethylene glycol for each part by weight of paracetamol; b) it is substantially anhydrous; and c) it forms a clear solution for injection with 4-10 parts by volume of water for each part by weight of paracetamol. The solutions disclosed are “substantially anhydrous” which, as disclosed in the said patent, is understood to mean a composition containing less than 0. 1% by weight of water. The solutions disclosed are expected to be very viscous. Hence, these solutions are to be diluted with water to provide the injection solution wherein each part by weight of paracetamol has, i) from 1 to 4 parts by volume of a low molecular weight alcohol, ii) from 1 to 5 parts by volume of a polyethylene glycol, and iii) from 4 to 10 parts by volume of water.
Example number 1 of the said patent describes the preparation of the concentrated anhydrous solution which has a paracetamol titer of about 210 mg per ml. Example number 2, describes dilution of this concentrated anhydrous solution to produce injection solutions. As calculated, the titer of paracetamol in the injection solutions is about 85.60 mg per ml of injection solutions.
PCT/IB2008/003925 relates to stable aqueous solution of paracetamol containing about 10 mg/1 ml, to be administered exclusively by intravenous infusion.
PCT/US2008/083458 relates to compositions containing 10 mg/ml of Paracetamol for exclusive, administration by intravenous infusion.
PCT/EP2002/011498 relates to ready-to-use highly stable paracetamol injectable solutions, prepared by mixing paracetamol, water, propylene glycol, and a citrate buffer wherein the concentration of paracetamol is up to 40 mg/ml for exclusive administration by intravenous infusion.
PCT/EP2002/002696 relates to aqueous parenteral solutions of paracetamol containing 1 to 17 grams of paracetamol per liter (i.e. 1 mg per ml to 17 mg per ml) exclusively to be administered by intravenous infusion.
PCT/EP2000/006871 relates to liquid pharmaceutical compositions comprising at least 10% w/v of paracetamol in anhydrous PEG 200. Viscosity of a 22% (w/v) solution Paracetamol as disclosed in example 1 has viscosity 168.4 cps and therefore is unsuitable for use as injectables.
EP2087909 describes ready to use paracetamol injectable solution containing maximum concentration of paracetamil of 1 gm/100 ml in distilled water and buffering agent for exclusive administration as intravenous infusion.
EP0916347 discloses injection solution of paracetamol and combinations of paracetamol with other substances like hyoscine-n-butyl bromide and codeine phosphate
Indian Patent Application No. 1746/MUM/2008 relates to a pharmaceutical formulation of paracetamol that provides easy administration to the patients. The above application claims paracetamol injection containing maximum concentration of paracetamol at 15% w/v using combinations of glycofurol and water. However these solutions do not deliver the required therapeutic dose of 500 mg in 2 to 3 ml.
Indian Patent Application No. 1532/DEL/2008 relates to administration of paracetamol through intravenous route in which paracetamol is solubilised in water for injection in combination with passive ingredients like buffers, isotonicity agents, etc. However these also do not provide the required therapeutic dose of 500 mg in 2 to 3 ml.
Indian Patent Application No. 1529/DEL/2008 relates to compositions of paracetamol and ofloxacin for administration through intravenous route employing an aqueous vehicle.
Indian Patent Application No. 1530/DEL/2008 describes compositions of paracetamol and ciprofloxacin in aqueous vehicle to be administered by intravenous route.
Indian Patent Application No.1531/DEL/2008 describes a composition of paracetamol and diclofenac sodium in aqueous vehicle for intravenous administration.
Indian Patent Application No. 2708/DEL/2006 comprises aqueous solution of therapeutic active substances; preferably paracetamol complexed with hydroxyl propyl beta cyclodextrin (HP-B-CD) encapsulated in physiologically and pharmaceutically acceptable oil containing conventional lipophilic surfactant which in turn being dispersed in aqueous medium containing known hydrophilic surfactant.
Indian Patent Application No. 3782/DELNP/2005 relates to a novel injectable formulation of paracetamol, comprising an aqueous solvent, buffering agent with a pKa between 4.5 and 6.5, isotonic agent and dimer of paracetamol wherein the said dimer is used for the stabilization of the formulation.
Indian Patent Application No. 8070/DELNP/2008 relates to an aqueous paracetamol solution for use by perfusion, comprising at least one substance that can react with phenolates.
Paracetamol is sparingly soluble in water, therefore various solvents like propylene glycol, polyethylene glycol 400, glyceryl formal, glycofurol and ethanol etc have been used in the prior art, since paracetamol shows higher solubility in these solvents as compare to water. However there is no prior art disclosing paracetamol injectables with 500 mg of paracetamol in a single dose of about 2 or 3 ml.
A solitary prior art namely IN1746/MUM/2008 reported the use of 44% v/v glycofurol in combination with 10% v/v alcohol (name of alcohol not disclosed) in combination with water to solubuilise a maximum of 150 mg/ml of paracetamol. The same prior art reports the use of 48% v/v glycofurol in combination with water to solubilize a maximum of 150 mg/ml paracetamol. The challenge before the pharmaceutical industry is to provide injections comprising greater than 150 mg/ml up to about 250 mg/ml paracetamol, so that the therapeutic dose of 500 mg can be delivered as an injection of 2 to 3 ml of the solution. Further despite such high concentrations, the injections have to be of viscosity not more than 28 CPS. This has not been achieved to date.